2-phenylbenzoxazole derivatives



United States Patent 3,551,443 Z-PHENYLBENZOXAZOLE DERIVATIVES Max Duennenberger, Frenkendorf, and Leonard Guglielmetti, Birsfelden, Switzerland, assignors to Ciba Limited, Basel, Switzerland, a Swiss company No Drawing. Continuation of application Ser. No. 538,242, Mar. 29, 1966. This application Oct. 30, 1968, Ser. No. 775,577

Int. Cl. C07d 85/48 US. Cl. 260-307 2 Claims ABSTRACT OF THE DISCLOSURE New compounds are provided which are represented by the formula wherein one symbol or two symbols, if belonging to different ring systems, of the series Y Y X X and X is a substituent selected from the group COOA, COOR or CONR R in which A represents a hydrogen atom, an alkali metal ion, an ammonium ion or an amine salt ion, R represents a hydrocarbon residue or polyalkylene oxide residue containing up to 20 carbon atoms, and R and R denote hydrogen or an alkyl residue containing up to 20 carbon atoms, with R and R together not containing more than 20 carbon atoms. One to three residues of the series Y Y Y Y X X X X and X to the extent that they do not already have the significance given above, denote a hydrogen atom, an alkyl group containing up to 4 carbon atoms or a halogen atom. The remaining X and Y symbols each denote a hydrogen atom.

The compounds of this invention are especially useful as ultraviolet absorbers in cosmetic preparations.

This application is a continuation of application Ser. No. 538,242, filed Mar. 29, 1966, now abandoned.

The present invention relates to the use of certain derivatives of 2-phenylbenzoxazole as ultraviolet absorbers cosmetic purposes. The subject of the invention further comprises special new 2-phenylbenzoxazole derivatives which are preferentially used, and their manufacture.

Various ultraviolet absorbers for cosmetic preparations have already been suggested, including some based on 2- phenylbenzoxazole, but these however in no case fully meet the practical requirements, either in respect of the absorption range or in respect of physiological harmlessness.

It has now been found that these disadvantages can surprisingly be overcome if one uses as protective agents against ultraviolet rays for cosmetic purposes such derivatives of Z-phenylbenzoxazole as have a free or functionally converted carboxylic acid group in one or two of the positions 5, 6, 2', 3 or 4 of the Z-phenylbenzoxazole ice (compare the schematic formula below) but not adjacent to one another.

(I) One symbol or two symbols, if belonging to different ring systems, of the series Y Y X X and X represent a substituent of the group COOA, COOR or CONR R in which A represents a hydrogen atom, an alkali metal ion, an ammonium ion or an amine salt ion, R represents a hydrocarbon residue or polyalkylene oxide residue containing up to 20 carbon atoms, and R and R denote hydrogen or an alkyl residue containing up to 20 carbon atoms, with R and R together not containing more than 20 carbon atoms, and

(II) One to three residues of the series Y Y Y Y X X X X and X to the extent that they do not already have the significance given under (I), denote a hydrogen atom, an alkyl group containing up to 18 carbon atoms, an alkoxy group containing up to 4 carbon atoms or a halogen atom, and the remaining X and Y symbols each denote a hydrogen atom.

To the extent that within the framework of the definition of the above Formula 2 dicarboxylic acids or their derivatives are considered, those types of compound are of predominant interest which correspond to Formula 3 in which Y or Y and X each represent substituents as defined under Formula 2.

Within the framework of the present invention preferred interest attaches to the new 2-phenylbenzoxazole derivatives of the monocarboxylic acid or monocarboxylic acid derivative type of formula N v1 v2 UP 1 I 0 5 V4 U4 in which:

(I) Only one symbol of the series U U V V or represents a substituent of the group COOA, COOR or CONR R in which A represents a hydrogen atom, an alkali metal ion, an ammonium ion or an amine salt ion, R represents a hydrocarbon residue or polyalkylene oxide residue containing up to 20 carbon atoms, and R and R represent hydrogen or an alkyl residue containing up to 20 carbon atoms, with R and R together not containing more than 20 carbon atoms, and

(11) One to three residues of the series U U U U V V V V V to the extent that they do not already have the significance given under (I), denote a hydrogen atom, an alkyl group containing up to 18 carbon atoms, an alkoxy group containing up to 4 carbon atoms, or a halogen atom, and the residual X and Y symbols each denote a hydrogen atom.

Amongst these new carboxylic acid derivatives there should particularly be stressed those in which the 2-phenylbenzoxazole, apart from a carboxyl function in positions 4 or 5, contains no further substituents, that is to say, compounds corresponding to the formula and in which U or V have the significance given under Formula 4(1).

Finally, an especial selection consists of compounds of Formulae 4 and in which the carboxylic acid groups or functionally converted carboxyl groups in positions 5 or 4 denote, as the substituents U or V (a) a substituent COOA in which A represents an amine salt ion of an aliphatic saturated amine containing up to 12 carbon atoms or,

(b) a substituent COOR{, in which R represents an alkyl residue containing 4 to 20 carbon atoms or a residue containing up to polyethylene oxide groups [-CH CH O].

With the framework of the above definition, possible carboxyl compounds of Z-phenylbenzoxazoles include those in which, as explained above, the carboxyl function is present as a carboxyl anion and the cation A represents a hydrogen ion, an alkali metal ion such as Na+, or K an ammonium ion or an amine salt ion. The latter are preferably represented by trialkanolamines, such as especially triethanolamine.

"Possible hydrocarbon residues R having up to carbon atoms are: alkyl residues such as for example straight-chain alkyl residues such as methyl, ethyl, propyl, hexyl, octyl, nonyl, dodecyl, octadecyl, preferably those having at least 4 C atoms, branched alkyl residues preferably having up to 8 carbon atoms such as for example isopropyl, tert. butyl, 2,2,4-trimethylpentyl and others.

Possible polyalkylene oxide residues are primarily polyethylene oxide residues, and here again those having up to 20 carbon atoms, preferably those having 2 to 4 polyethylene oxide groups [CH CH O], whose terminal hydroxyl group may be etherified with a monofunctional aliphatic saturated alcohol containing 1-8 carbon atoms.

In the case of the carboxylic acid amide type, R and R may be alkyl residues as listed for R above; as the most important instances there may be named ethyl, butyl and octyl.

Substituents of the series Y Y Y Y X X X X and X to the extent that they are not already represented by a carboxyl function, may according to the definition inter alia represent an alkyl group containing up to 18 carbon atoms, with possible structures including those listed above under R Amongst alkoxy groups, the methoxy, ethoxy, propoxy and butoxy groups should be named as being of particular interest. Amongst the halogens, chlorine and bromine are predominantly of practical significance, and it is however advisable for there only to be one such halogen atom pre ent in the molecule in each case.

The following may be named by way of examples of typical compounds according to the present invention: 2- phenylbenzoxazole 5 carboxylic acid methyl ester, 2- phenylbenzoxazole-S-carboxylic acid, 2-phenylbenzoxazole-4-carboxylic acid, 2-phenyl-5-chlorobenzoxazole-4'- carboxylic acid, Z-phenyl-S-tert. butylbenzoxazole-4-carboxylic acid, 2-phenyl-S-rnethylbenzoxazole-4-carboxylic acid, 2-phenylbenzoxazole-S-carboxylic acid-n-octyl ester, Z-phenylbenzoxazole-6-carboxylic acid, 2-phenylbenzoxa- Zole-6-carboxylie acid methyl ester, 2-phenylbenzoxazole 5,4'-di(carboxylic acid methyl esttr), 2-phenylbenzoxazole-6,4-di(carboxylic acid methyl ester) triethanolamine salt of 2-phenylbenzoxazole-S-carbr xylic acid, triethanolamine salt of 2-phenylbenzoxazole-w-carboxylic acid.

The 2-phenylbenzoxazoles define [1 above may be produced analogously to processes which are in themselves known, by reacting equimolar amounts of ano-hydroxyaminobenzene of Formula 6 with a benzene monocarboxylic acid of Formula 7 or its halide:

In these formulae all symblos have the same significance as stated for Formula 2, with the exception that the X and Y symbols must not represent free COOH groups or their salts, but instead the carboxylic acid groups must be present in a protected form. Examples of such protccted carboxyl groups are carboxylic acid ester groups, carboxylic acid amide groups, urethane groups or carboxylic acid nitrile groups or other protected carboxyl functions of comparable reactivity.

Depending on the physical and chemical nature of the components the reaction may take place in bulk, such as for example in the melt or in solution, and in the latter case suitable solvents are of course all those which on the one hand exert a sufficient dissolving etTect and which on the other hand are chemically inert to the reaction components (for example dichlorobenzenes). The possible temperature range for the reaction largely has to be suited to the reactivity of the components and in practice the range of to 250 C. is generally appropriate. The reaction is preferably carried out in the presence of catalysts or auxiliary substances which serve to eliminate water or favour the elimination of water such as for example boric acid, p-toluenesulphonic acid, phosphoric acids, sulphuric acid and the like.

The 2-phenylbenzoxazole derivatives to be used according to the invention are appropriate means for protecting the skin against ultraviolet radiation. They may be converted to stable and ready-to-use cosmetic preparations 1n a manner which is in itself known. They are appropriately mixed with carrier substances, emulsified, or preferably dissolved in the carriers. Such carriers may be present in a liquid or semi-solid form. They comprise liquid organic diluents, for example organic solvents such as alcohols or ketones, for example ethanol, isopropanol, glycerine, cyclohexanol, methylcyclohexanol, as well as trrchlorethylene, petrol, esters of vegetable or animal origin such. as vegetable or animal oils and fats, for example groundnut oil, cocoa butter or lanoline. It is also possible to use mineral solvents such as parafiin oil, white mineral oil, white petroleum oil or white petroleum jelly. If an aqueous dispersion of the protective agent is desired, then the substance can be directly finely dispersed in water with the aid of suitable dispersing agents or completely or partially dissolved in an organic carrier (see above) and then dispersed or emulsified in water. Of course further substances, for example skin cosmetics, insect repellents, deodorants, scents and dyestuffs may be added to such mixtures and preparations. By suitable choice of one or more carriers together with, optionally, further additives one obtains solutions, ointments, pastes, creams, oils or emulsions.

Using suitable solvents, for example fluorochloralkanes, it is also possible to produce spray preparations (so-called aerosol sprays) which may be stored in closed containers and be applied directly from these to the areas of skin to be protected by actuating a valve.

The cosmetic preparation may, depending on its nature, contain amounts of the 2-phenylbenzoxazole to be used according to the invention which vary between quite considerable limits.

However, for most practical purposes amounts of between 0.05 and 5, preferably 1 to 3, percent by weight of the Z-phenylbenzoxazole derivative, relative to the total amount of preparation, are generally appropriate.

The 2-phenylbenzoxazole derivatives to be used as protective agents according to the present invention are particularly well suited to being used as skin protecting agents because on the one hand they are readily soluble in organic solvents such as are used for cosmetic purposes, whereas on the other hand they largely absorbe the ultraviolet rays of wavelength up to about 330 m which cause reddening of the skin whilst having no effect on the rays of higher wavelengths of 330 to about 400 m whose tanning effect is generally desired.

In the examples which follow the parts denote parts by weight unless otherwise stated, and the percentages denote percentages by weight.

EXAMPLE 1 33.4 parts of methyl 4-hydroxy-5-aminobenzoate are stirred for 1 hour at 150 C. with 28.1 parts of benzoyl chloride in 160 parts of dichlorobenzene. The dichlorobenzene is then distilled off, 1 part of boric acid is added to the reaction mixture, and the temperature raised to 2002l0 C. In order to eliminate water the mixture is stirred for 2 hours at the same temperature, and thereafter 40 parts of dichlorobenzene are added at 160 C. whereupon the product of formula precipitates in the form of almost colourless crystals. In order to complete the crystallisation a further 200 parts of methanol are added to the crystal sludge, with stirring. The product is filtered off, washed with 100 parts of methanol and dried in vacuo at 80 to 110 C. Yield, about 40 parts. Melting point, 157 to 158 C.

C H O N: calculated (percent): C, 71.14; H, 4.37; N, 5.53. Found (percent): C, 70.95; H, 4.45; N, 5.54.

EXAMPLE 2 25.3 parts of the compound of Formula 8 are stirred for 2 hours under reflux with a mixture'of 150 parts of ethanol, 30 parts of water and 10 parts of sodium hydroxide. The mixture is cooled to room temperature and the sodium salt of the carboxylic acid is filtered off and washed with 50 parts of ethanol. In order to produce the free acid the sodium salt is dissolved in 500 parts of water at 90 C.,

and acidified with concentrated hydrochloric acid, whereupon the product of formula precipitates in the form of colourless crystals. Yield: about 23 parts. Melting point, 242 to 243 C.

C H O N: calculated (percent): C, 70.29; H. 3.79; N, 5.86. Found (percent): C, 70.36; H, 3.67; N, 5.83.

EXAMPLE 3 10.9 parts of 1-amino-2-hydroxybenzene, 18 parts of monoethyl terephthalate and 0.5 parts of boric acid are slowly heated to 210 C. with 1 00 parts of diethylene glycol diethyl ether in a stirred flask, during the course of which the resulting water is distilled off together with the diethylene glycol diethyl ether. The mixture is stirred for a further 2 hours at the same temperature, then cooled to C., 300 parts of dioxane and 12 parts of sodium hydroxide are added to the mixture and the mixture stirred for a. further 1 hour at 95 C. The product is cooled to room temperature, filtered and washed with 50 parts of dioxane. The sodium salt is dissolved in 350 parts of water, a few undissolved crystals are filtered off, and the filtrate acidified with concentrated hydrochloric acid whereupon the product of formula H O 0 C- separates out in the form of colourless crystals. Yield, about 20 parts. An analytical product which was twice recrystallised from dioxane/water melts at 31031l C.

C H O N calculated (percent): C, 70.29; H, 3.79; N, 5.86. Found (percent): C, 70.40; H, 3.70; N, 5.80.

EXAMPLE 4 If in Example 3 the corresponding amount of l-amino- 2-hydroxy-4-tert. butylbenzene is used instead of l-amino- 2-hydroxybenzene, then the product of formula is obtained in corresponding purity and yield; melting point 179 to 180 C.

C18H17O3NI calculated (percent): C, 73.20; H, 5.80;

N, 4.74. Found (percent): C, 72.94; H, 5.88; N, 4.73.

EXAMPLE 5 60 parts of the compound of Formula 8 are stirred for 6 hours at to C. with 1 part of sodium ethylate in 300 parts of n-octanol. The mixture is cooled to 80 C. and treated with 300 parts of ethanol followed by 1 00 parts of water. The product of formula The compounds represented by the formulae given below may be obtained in an analogous manner.

Melting point: 93 to 94 C.

Calculated (percent): C, 73.76; H, 6.19; N, 4.53. Found percent): C, 73.45; H, 6.10; N, 4.74.

Melting point: 85 to 86 C.

Melting point: 166 to 167 C. Calculated (percent): C, 76.81; H, 8.43; N, 6.89. Found (percent): C, 76.55; H, 8.67; N, 7.01.

Calculated (percent): C, 75.18; H, 7.17; N, 3.99. Found (percent): C, 75.30; H, 7.11; N, 4.04.

The following compounds are also produced in an analogous manner.

17 N CH3 C- C-CII: Q,

Melting point: 260 to 262 C. C H O N: calculated (percent): C, 73.20; H, 5.80; N, 4.74. Found (percent): C, 73.23; H, 5.76; N, 4.69.

Melting point: 130 to 132 C. C H O N: calculated (percent): C, 73.76; H, 6.19; N, 4.53. Found (percent): C, 73.56; H, 6.01; N, 4.71.

CIIaOOC- Melting point: 228 to 229 C. C H O N: calculated (percent): C, 65.59; H, 4.21; N, 4.50. Found (percent): C, 65.30; H, 4.15; N, 4.56.

Melting point 219 to 220 C. C1'1H1305NI calculated (percent): C, 65.59; H, 4.21; N, 4.50. Found (percent): C, 65.53; H, 4.19; N, 4.40.

EXAMPLE 6 parts of the compound of Formula 9 are dissolved in 470 parts of water and 69 parts of triethanolamine. The resulting aqueous solution of the triethanolamine salt of formula may be used for the most diverse cosmetic formulations.

EXAMPLE 7 (Cosmetic formulation) Percent Cetiol (=mixture of esters of unsaturated fatty acids obtained from spermaceti and principally containing oleyl oleate) 10.00 Stearin 6.00 Water 68.95 KOH 0.45

Triethanolamine 1.10 Solution prepared according to Example 6 (Formula 21) 13.50

The sun lotion so obtained very eifectively retains harmful radiation in the sense of rays causing burns, but at the same time effectively transmits tanning radiation.

EXAMPLE 8 Percent Propylene glycol 5.00 Water 56.50 Fine spirit 25.00 Solution prepared according to Example 6 13.50

The sun lotion so obtained has a similar effect to that given in Example 7.

EXAMPLE 9 EXAMPLE 1O 10 parts of isopropyltetrahydrofurfuryl adipate, 5 parts of benzoic acid diethylamide, 8 parts of dimethyl phthalate and 5 parts of one of the compounds of Formula 14 or 15 are dissolved in 36 parts of groundnut oil and 36 parts of paraffin oil. A sun lotion having an insect repellent effect is obtained.

EXAMPLE 11 4 parts of one of the compounds of Formula 11 or 13, 10 parts of glycerine monostearate, 4 parts of cetyl alcohol, 1 part of sodium cetyl sulphate, 1 part of stearic acid and 5 parts of glycerine are intimately mixed and emulsified in 75 parts of water.

An emulsion is obtained which is very suitable as a nongreasy skin cream and which protects the treated areas against sun rays.

EXAMPLE 12 5 parts of isopropyltetrahydrofurfuryl adipate, 5 parts of toluic acid diethylamide, 3 parts of the compound of Formula 14, 6 parts of cetyl alcohol, 14 parts of white petroleum oil, 10 parts of white beeswax, 14 parts of lanolin, 3 parts of cocoa butter, 39.7 parts of water, and 0.3

parts of sodium benzoate are converted to an insect repellent sun-protecting cream by intimate mixing.

EXAMPLE 13 A film of approximately 60 2 thickness is produced from a 10% strength solution of acetylcellulose in acetone, which contains 1% of the compound of Formula 9 calculated relative to acetylcellulose. After drying, a part of the film obtained is irradiated in a Fadeometer for 100 hours. The following figures are obtained for the percentage transmission:

Light transmission in percent Wavelength in m. Exposed Unexposed 280 to 320 0 0 90 90 340 to 400 90 90 EXAMPLE 14 In order to produce an emusion which may be used as a cosmetic sun-protecting agent, the oil phase (A) and the aqueous phase (B) of the composition given below are required:

Colloidally dispersed mixture of 90% cetyl alcohol and stearyl alcohol and sodium lauryl sul- Parts The moltenoil phase A, warmed to 70 C., is added to the aqueous phase B warmed to 75 C. with vigorous stirring. The emulsion is rinsed in cold water and perfumed (0.3 part of perfume).

EXAMPLE 15 A solution of the following composition is prepared by Working in the usual manner:

Parts Compound of Formula 13 3 Polyethylene glycol of molecular weight 300 40 Propylene glycol 25 Isopropyl myristate 2.5 Ethanol 29.2 Perfume 0.3

This solution may be used as a means of protecting the skin against ultraviolet radiation. It is preferably applied to the skin by means of a suitable spray device.

We claim:

1. A compound of the formula 2. A compound of the formula N 1 C OO0OH. HaCOOC- References Cited UNITED STATES PATENTS 3/ 1956 Sartori 260-304 OTHER REFERENCES C. A. 29: 3851' -Abstract of French Pat. 769,405 of Aug. 25, 1934.

ALEX MAZEL, Primary Examiner R. V. RUSH, Assistant Examiner US. Cl. X.R. 424-272 

